{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:35:11Z","timestamp":1789641311348,"version":"4.0.0"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM144368"],"award-info":[{"award-number":["R01 GM144368"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM133865"],"award-info":[{"award-number":["R01 GM133865"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 R01NS119426"],"award-info":[{"award-number":["R01 R01NS119426"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R35 GM139566"],"award-info":[{"award-number":["R35 GM139566"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003138","name":"Mitochondrial Research Guild","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003138","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Academy of Medical Science"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and\/or basal ganglia. Recent studies in the <jats:italic>Ndufs4<\/jats:italic>(-\/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of <jats:italic>Ndufs4<\/jats:italic>(-\/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in <jats:italic>Ndufs4<\/jats:italic>(-\/-) disease pathogenesis. We crossed <jats:italic>Ndufs4<\/jats:italic>(-\/-) mice with mice expressing a null form of interleukin 2 receptor gamma (<jats:italic>Il2rg<\/jats:italic>) and monitored disease onset and progression. <jats:italic>Il2rg<\/jats:italic> knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system\u2019s key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between <jats:italic>Ndufs4<\/jats:italic>(-\/-)\/<jats:italic>Il2rg<\/jats:italic>(WT) and <jats:italic>Ndufs4<\/jats:italic>(-\/-)\/<jats:italic>Il2rg<\/jats:italic>(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in <jats:italic>Ndufs4<\/jats:italic>(-\/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte\/macrophage innate immune system.<\/jats:p>","DOI":"10.1371\/journal.pone.0324268","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T17:43:31Z","timestamp":1749577411000},"page":"e0324268","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-\/-) model of Leigh syndrome"],"prefix":"10.1371","volume":"20","author":[{"given":"Allison 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Shien","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip G.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surojit","family":"Sarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Kalia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1942-3674","authenticated-orcid":true,"given":"Simon C.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"issue":"1","key":"pone.0324268.ref001","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1186\/s13023-021-02029-3","article-title":"Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases","volume":"16","author":"A Ardissone","year":"2021","journal-title":"Orphanet J Rare Dis"},{"issue":"22","key":"pone.0324268.ref002","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.4103\/0366-6999.245265","article-title":"Clinical, neuroimaging, and pathological analyses of 13 Chinese Leigh syndrome patients with mitochondrial DNA mutations","volume":"131","author":"X-L Yu","year":"2018","journal-title":"Chin Med J (Engl)"},{"key":"pone.0324268.ref003","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pediatrneurol.2016.10.006","article-title":"Cause of death in children with mitochondrial diseases","volume":"66","author":"S Eom","year":"2017","journal-title":"Pediatr Neurol"},{"issue":"1","key":"pone.0324268.ref004","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1186\/s13023-022-02495-3","article-title":"The immune system as a driver of mitochondrial disease pathogenesis: a review 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